Hemorrhage induced by antithrombotic agents: new insights from a real-world pharmacovigilance study.

BACKGROUND: Hemorrhage represents the most common and serious side effect of antithrombotic agents. Many studies have compared the risk of bleeding between different antithrombotic agents, but analysis of time-to-onset for hemorrhage induced by these drugs is yet sparse. METHODS: We conducted a retrospective study based on the adverse drug reaction reports on antithrombotic agents collected by the Henan Adverse Drug Reaction Monitoring Center. We assessed the reporting odds ratio to determine the disproportionate reporting signals for bleeding and the Weibull shape parameter was used to evaluate the time-to-onset data. RESULTS: In the signal detection, crude low molecular weight heparin-hemorrhage was found as a positive signal. The hemorrhage for most antithrombotic agents was random failure profiles. In particular, the hazard of hemorrhage decreased over time for warfarin and clopidogrel and increased for alteplase, nadroparin, and dipyridamole. CONCLUSION: We found that the risk of bleeding in patients taking Crude low molecular weight heparins was significantly higher compared to other antithrombotic agents, but with a small magnificence, which may be attributed to the severely irrational use of this medication under improper management. Statistics in days, results showed that the risk of bleeding decreased over time for warfarin and clopidogrel and increased for alteplase, nadroparin, and dipyridamole.

Rivaroxaban versus nadroparin for thromboprophylaxis following thoracic surgery for lung cancer: A randomized, noninferiority trial.

The benefit of rivaroxaban in thromboprophylaxis after oncologic lung surgery remains unknown. To evaluate the efficacy and safety of rivaroxaban, patients who underwent thoracic surgery for lung cancer were enrolled, and randomly assigned to rivaroxaban or nadroparin groups in a 1:1 ratio; anticoagulants were initiated 12-24 h after surgery and continued until discharge. Four hundred participants were required according to a noninferiority margin of 2%, assuming venous thromboembolism (VTE) occurrence rates of 6.0% and 12.6% for patients in the rivaroxaban and nadroparin groups, respectively. The primary efficacy outcome was any VTE during the treatment and 30-day follow-up periods. The safety outcome was any on-treatment bleeding event. Finally, 403 patients were randomized (intention-to-treat [ITT] population), with 381 included in per-protocol (PP) population. The primary efficacy outcomes occurred in 12.5% (25/200) of the rivaroxaban group and 17.7% (36/203) of the nadroparin group (absolute risk reduction, -5.2%; 95% confidence interval [CI], [-12.2-1.7]), indicating the noninferiority of rivaroxaban in ITT population. Sensitivity analysis was performed in the PP population and yielded similar results, confirming the noninferiority of rivaroxaban. In the safety analysis population, the incidence of any on-treatment bleeding events did not differ significantly between the groups (12.2% for rivaroxaban vs. 7.0% for nadroparin; relative risk [RR], 1.9; 95% CI, [0.9-3.7]; p = .08), including major bleeding (9.7% vs. 6.5%; RR, 1.6 [95% CI, 0.9-3.7]; p = .24), and nonmajor bleeding (2.6% vs. 0.5%; RR, 5.2 [95% CI, 0.6-45.2]; p = .13). Rivaroxaban for thromboprophylaxis after oncologic lung surgery was shown to be noninferior to nadroparin.

Low and Highly Variable Exposure to Prophylactic LMWH Nadroparin in Critically Ill Patients: Back to the Drawing Board for Prophylactic Dosing?

BACKGROUND AND OBJECTIVE: Low-molecular-weight heparins are routinely administered to patients in the intensive care unit to prevent venous thromboembolisms. There is considerable evidence that low-molecular-weight heparin doses should be personalised based on anti-Xa levels, but pharmacokinetic data in intensive care unit patients are lacking. This study aimed to characterise the pharmacokinetics and associated variability of the low-molecular-weight heparin nadroparin in critically ill patients. METHODS: Critically ill adult patients who were admitted to the intensive care unit and received nadroparin for prophylaxis of venous thromboembolism were included in a study. Population pharmacokinetic analysis was performed by means of parametric non-linear mixed-effects modelling (NONMEM). RESULTS: A total of 30 patients were enrolled with 12 patients undergoing continuous veno-venous hemodialysis and 18 patients not undergoing continuous veno-venous hemodialysis. Very high variability in pharmacokinetics was observed with an inter-individual variability in the volume of distribution of 63.7% (95% confidence interval 46.5-90.6), clearance of 166% (95% confidence interval 84.7-280) and relative bioavailability of 40.2% (95% confidence interval 29.5-52.6). We found that standard doses of 2850 IE and 5700 IE of nadroparin resulted in sub-prophylactic exposure in critically ill patients. CONCLUSIONS: Low exposure and highly variable pharmacokinetics of nadroparin were observed in intensive care unit patients treated with a prophylactic dose. It can be debated whether nadroparin is currently dosed optimally in intensive care unit patients and our findings encourage the investigation of higher and tailored dosing of nadroparin in the critically ill.

Trough anti-Xa activity after intermediate dose nadroparin for thrombosis prophylaxis in critically ill patients with COVID-19 and acute kidney injury.

Our objective was to assess the incidence of drug bioaccumulation in critically ill COVID-19 patients with AKI receiving intermediate dose nadroparin for thrombosis prophylaxis. We conducted a Prospective cohort study of critically ill COVID-19 patients. In patients on intermediate dose nadroparin (5700 IU once daily) we assessed the incidence of bioaccumulation (trough anti-Xa level > 0.2 IU/mL) stratified according to presence of AKI. We quantified this association using multilevel analyses. To assess robustness of our observations, we explored the association between AKI and anti-Xa activity in patients receiving high dose nadroparin (> 5700 IU). 108 patients received intermediate dose nadroparin, of whom 24 had AKI during 36 anti-Xa measurements. One patient with AKI (4.2% [95%CI 0.1-21%]) and 1 without (1.2% [95%CI 0.03-6.5%]) developed bioaccumulation (p = 0.39). Development of AKI was associated with a mean increase of 0.04 (95%CI 0.02-0.05) IU/ml anti-Xa activity. There was no statistically significant association between anti-Xa activity and AKI in 51 patients on high dose nadroparin. There were four major bleeding events, all in patients on high dose nadroparin. In conclusion, Bioaccumulation of an intermediate dose nadroparin did not occur to a significant extent in critically ill patients with COVID-19 complicated by AKI. Dose adjustment in AKI may be unnecessary.

Critical appraisal of evidence for anti-Xa monitoring and dosing of low-molecular-weight heparin in renal insufficiency.

INTRODUCTION: Several guidelines advise to monitor therapeutic LMWH therapy with peak anti-Xa concentrations in renal insufficiency with subsequent dose adjustments. A better understanding of the clinical association between peak anti-Xa concentrations and clinical outcomes is mandatory, because misunderstanding this association could lead to erroneous, and potentially even harmful, LMWH dose adjustments. AREAS COVERED: We reviewed the evidence of the widely applied therapeutic window for anti-Xa peak concentrations and report on the evidence for pharmacokinetic dose reduction in renal insufficiency, limitations of peak and trough anti-Xa concentration monitoring. EXPERT OPINION: The added value of peak anti-Xa monitoring in patients with renal insufficiency, receiving a dose reduced for pharmacokinetic changes, is not supported by data. Enoxaparin and nadroparin should be adjusted to 50-65% and 75-85% of the original dose for patients with a creatinine clearance (CrCL) of <30 ml/min and 30-60 ml/min, respectively. Tinzaparin should be adjusted to around 50% of the original dose for patients with a CrCL of <30 ml/min. In case anti-Xa monitoring is applied, trough concentration anti-Xa monitoring is preferred over peak monitoring, aiming at a maximum concentration of 0.4 IU/mL for once-daily dosed tinzaparin and 0.5 IU/mL for twice-daily dosed enoxaparin and nadroparin.

[Hyperkalemia due to low-molecular-weight heparin]. / Hyperkaliëmie bij laag-molecuulgewicht heparine.

BACKGROUND: The cause of hyperkalemia is frequently iatrogenic. Patient's prescriptions should therefore be checked in the analysis of the hyperkalemia. Low-molecular-weight heparin is not often suspected to cause this. CASE DESCRIPTION: A 64-year-old man, hospitalized because of a complicated clinical course of pancreatitis, developed an acute severe hyperkalemia. Further analysis was susceptive for hypoaldosteronism, which was confirmed with biochemical testing. The only drug that could cause hyperkalemia in this case was nadroparin, which was prescribed because of vena lienalis and a superior mesenteric vein thrombosis. A rechallenge with nadroparin showed a rapid rise in serum potassium, confirming our suspicion. CONCLUSION: In the diagnostic work-up of hyperkalemia, hypoaldosteronism should be considered in patients using LMWH. In particular when other risk factors for hyperkalemia are present, monitoring of potassium could be advised in patients receiving these agents.

Localized and Generalized Skin Adverse Drug Reactions to Nadroparin Calcium Injection in 6 Cases of Pregnant Women.

Background: Despite the increasing number of skin adverse drug reactions caused by nadroparin calcium have been reported, mostly, little is known regarding of their details of clinical characteristics, especially for generalized skin adverse drug reactions. We sought to evaluate localized and generalized characteristics of the skin adverse drug reaction to nadroparin calcium injection in pregnant women. Methods: A retrospective study was conducted on 6 pregnant women, who experienced localized and generalized skin adverse drug reactions during long-term nadroparin calcium injection. The patients' clinical and imaging information were retrieved from medical records. The skin prick test, patch test, and intradermal test were performed after they stopped lactation. Causality assessment of suspected adverse drug reactions was performed on these cases. Results: The average total dose of nadroparin calcium injection in the 6 cases was 64.17 ± 22.66. Localized skin adverse drug reaction, manifested as erythema at the injection point, appeared after 47.5 ± 17.4 days of subcutaneous injection of nadroparin calcium. Generalized urticaria-like lesions, progressing from the injection site on the abdomen, appeared in 5.17 ± 3.60 days after the first appearance of localized reaction, while laboratory test results revealed essential peripheral blood eosinophilia. All rashes in the 6 cases subsided in 2-5 weeks after drug withdrawal. After delivery, 5 of 6 cases received complete skin tests to evaluate drug hypersensitivity. Results presented positive in the intradermal test within 7 days. Both the skin prick test and skin patch test were negative. Localized skin reactions and generalized urticaria-like adverse drug reactions were considered as definitely and probably caused by nadroparin calcium injection, respectively. Conclusion: Subcutaneous injection of nadroparin calcium in pregnant women appears to be at risk of localized and generalized urticaria-like adverse drug reaction. It is important to follow up the pregnant woman during nadroparin calcium injection for evaluating adverse drug reactions. Timely detection of symptoms is pivotal in early diagnosis and treatment of adverse drug reactions.

Bleeding complications of thromboprophylaxis with dabigatran, nadroparin or rivaroxaban for 6 weeks after total knee arthroplasty surgery: a randomised pilot study.

OBJECTIVES: For the non-vitamin-K oral anticoagulants, data on bleeding when used for 42 days as thromboprophylaxis after total knee arthroplasty (TKA) are scarce. This pilot study assessed feasibility of a multicentre randomised clinical trial to evaluate major and clinically relevant non-major bleeding during 42-day use of dabigatran, nadroparin and rivaroxaban after TKA. PATIENTS AND METHODS: In 70 weeks, between July 2012 and November 2013, 198 TKA patients were screened for eligibility in the Martini Hospital (Groningen, the Netherlands). Patients were randomly assigned to dabigatran (n=45), nadroparin (n=45) or rivaroxaban (n=48). The primary outcome was the combined endpoint of major bleeding and clinically relevant non-major bleeding. Secondary endpoints of this study were the occurrence of clinical venous thromboembolism (VTE) (pulmonary embolism or deep venous thrombosis), compliance, duration of hospital stay, rehospitalisation, adverse events and Knee Injury and Osteoarthritis Outcome Score (KOOS). RESULTS: The primary outcome was observed in 33.3% (95% CI 20.0% to 49.0%), 24.4% (95% CI 12.9% to 39.5%) and 27.1% (95% CI 15.3% to 41.8%) of patients who received dabigatran, nadroparin or rivaroxaban, respectively (p=0.67). Major bleeding was found in two patients who received nadroparin (p=0.21). Clinically relevant non-major bleeding was observed in 33.3% (95% CI 20.0% to 49.0%), 22.2% (95% CI 11.2% to 37.1%) and 27.1% (95% CI 15.3% to 41.8%) for dabigatran, nadroparin and rivaroxaban, respectively (p=0.51). Wound haematoma was the most observed bleeding event. VTE was found in one patient who received dabigatran (p=0.65). The presurgery and postsurgery KOOS qQuestionnaires were available for 32 (71%), 35 (77%) and 35 (73%) patients for dabigatran, nadroparin and rivaroxaban, respectively. KOOS was highly variable, and no significant difference between treatment groups in mean improvement was observed. CONCLUSIONS: A multicentre clinical trial may be feasible. However, investments will be substantial. No differences in major and clinically relevant non-major bleeding events were found between dabigatran, nadroparin and rivaroxaban during 42 days after TKA. KOOS may not be suitable to detect functional loss due to bleeding. TRIAL REGISTRATION NUMBER: NCT01431456.

Effect of 3 different anticoagulants on hidden blood loss during total hip arthroplasty after tranexamic acid.

Comparison of different anticoagulants in blood management and complications with tranexamic acid (TXA) in total hip arthroplasty (THA) is unclear. Our aim was to compare the efficacy and safety among receiving nadroparin calcium, enoxaparin sodium or rivaroxaban after TXA in THA.150 patients undergoing primary unilateral THA were received 15 mg/kg intravenous TXA (IV-TXA) before skin incision, followed by 1 of nadroparin calcium (Group A), enoxaparin sodium (Group B), or rivaroxaban (Group C) randomly during hospitalization. The primary outcome was hidden blood loss (HBL). Other outcomes such as the maximum hemoglobin (Hb) drop, total blood loss (TBL), the volume of drainage, transfusion rate, length of hospital stay (LOS), and complications were also compared.There were no statistically significant differences in HBL, the maximum hemoglobin (Hb) drop, transfusion rate, and complications among 3 groups. LOS was significantly higher for patients in Group B than Group A (P = .026). Neither deep venous thrombosis (DVT) nor pulmonary embolism (PE) occurred in any group.There were no differences in efficacy and safety in patients undergoing THA receiving nadroparin calcium, enoxaparin sodium, or rivaroxaban after anti-fibrinolysis with TXA.

Efficacy and Safety of Nadroparin Calcium-Warfarin Sequential Anticoagulation in Portal Vein Thrombosis in Cirrhotic Patients: A Randomized Controlled Trial.

INTRODUCTION: Anticoagulation therapy in portal vein thrombosis (PVT) in patients with cirrhosis is still a matter of debate. Therefore, the aim of this work was to evaluate the efficacy and safety of nadroparin calcium-warfarin sequential (NWS) anticoagulation therapy in cirrhotic patients and to find an optimal anticoagulation strategy. METHODS: Consecutive cirrhotic patients with PVT who have not received anticoagulation therapy were randomly divided into the NWS therapy group (1-month nadroparin calcium by subcutaneous injection followed by 5-month warfarin by oral administration) and control group (no anticoagulation therapy). Overall recanalization rate of PVT and risks of bleeding were evaluated at the sixth month. RESULTS: Among 64 patients, complete or partial recanalization of PVT was observed in 20/32 NSW therapy group patients vs 11/32 control group patients (62.5% vs 34.4%, P = 0.024), with no statistically significant difference in bleeding rate. Child-Pugh score (P = 0.023), D-dimer < 2.00 µg/mL (P = 0.020), and NWS anticoagulation therapy (P = 0.004) were predictors associated with the recanalization. NWS anticoagulation therapy (P = 0.008) was an independent predicting factor of recanalization. In the NWS therapy group, the Child-Pugh score (P = 0.007) and albumin level (P = 0.004) were improved in the sixth month. DISCUSSION: NWS anticoagulation therapy was effective and safe in PVT patients with cirrhosis and could increase the level of albumin. NWS therapy is safe and easily accepted.

Comparison of the Effects of Low-Molecular-Weight Heparin and Fondaparinux on Liver Function in Patients With Pulmonary Embolism.

Hepatotoxicity with low-molecular-weight heparin (LMWH) or fondaparinux is a relatively common adverse reaction. This study assessed the effects of LMWH and fondaparinux on liver function in patients with pulmonary embolism based on a retrospective cohort. As a result, a total of 463 patients with pulmonary embolism and treated with LMWH (enoxaparin sodium or nadroparin calcium) or fondaparinux sodium were included. Liver dysfunction was identified in 79 patients (17.1%), of whom 97.5% had grade 1 drug-induced liver injury (DILI) and 2.5% had grade 2 DILI. The results showed that liver dysfunction usually occurred in the first week after anticoagulant administration, and the liver tests of all patients with liver dysfunction gradually recovered or alleviated at discharge. The multivariable logistic regression analysis indicated that a longer treatment course and hepatitis B surface antigen-positive (HBsAg+) were risk factors for liver dysfunction (P < .05). Moreover, nadroparin calcium had the highest risk of liver dysfunction, approximately 2.2 times (95% confidence interval [CI], 1.1740-4.224; P = .015) that of enoxaparin sodium. In conclusion, nearly one-fifth and 10% of patients prescribed with LMWH or fondaparinux, respectively, for pulmonary embolism had liver dysfunction, mainly with mild liver injury and characterized by self-limited elevated serum transaminase levels. Hence, during the 3 anticoagulant applications, we should pay more attention to the monitoring of liver function in the first week and transit to oral anticoagulants if possible, especially for patients who are HBsAg+ or suffering from other liver diseases.

Clinical study on low-molecular weight heparin infusion as anticoagulation for nocturnal home haemodialysis.

AIM: This study was conducted to evaluate low-molecular weight heparin (LMWH) as anticoagulation for nocturnal home haemodialysis (NHHD). While its longer half-life may cause drug accumulation in frequent dialysis, the essential need of a supplementary intra-dialytic bolus for the sleeping patients also renders LMWH's use impractical. METHODS: The recruited patients, who were on alternate-day 8 h haemodialysis, were randomized to receive either nadroparin or unfractionated heparin (UFH) for a week. They underwent crossover to receive the alternate anticoagulant in the next week. A nadroparin infusion regimen was adopted to enhance its practicability, which consisted of a loading dose of 35 IU/kg and a continuous infusion of 10 IU/kg per hour for 6 h. RESULTS: A total of 12 NHHD patients were recruited. With nadroparin infusion, the mean anti-Xa levels at the 2nd , 4th , 6th and 8th hours of dialysis were 0.46 ± 0.11, 0.55 ± 0.14, 0.61 ± 0.15 and 0.45 ± 0.15 IU/mL respectively. Comparing to UFH, which offered satisfactory anticoagulation according to the activated partial thromboplastin time, nadroparin-treated dialysis achieved similar thrombus scores and dialyser urea/creatinine clearances at the end of haemodialysis. During the post-dialysis period, one patient demonstrated residual LMWH effect (anti-Xa level 0.09 IU/mL) on the next day, whereas none had detectable anti-Xa activities 2 days afterwards upon next dialysis. CONCLUSIONS: Low-molecular weight heparin infusion is practical and effective as anticoagulation for NHHD. It can be safely used in an alternate-day haemodialysis schedule. A close monitoring for LMWH accumulation is recommended if long dialysis is performed daily.

Major bleeding risks of different low-molecular-weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis.

Essentials Low-molecular-weight-heparins (LMWH) kinetics differ which may result in different bleeding risks. A cohort of 12 934 venous thrombosis patients on LMWH was followed until major bleeding. The absolute major bleeding risk was low among patients registered at the anticoagulation clinic. Once-daily dosing was associated with a lower bleeding risk as compared with twice-daily. SUMMARY: Background Low-molecular-weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events. Objectives To determine major bleeding risks for different LMWH agents and dosing schedules. Methods A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center. Results The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7-3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2-17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0-fold increased major bleeding risk (95% CI, 0.8-5.1) as compared with a nadroparin o.d. dosing schedule. Conclusions Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials.

Comparative Analysis of the Suspected Heparin-Induced Thrombocytopenia Level in Korea.

The primary objective of our study was to evaluate the frequency of suspected heparin-induced thrombocytopenia (HIT) among patients treated with different formulations of heparin and investigate the factors that affect the incidence of HIT. This study is an electronic medical record (EMR)-based large-scale retrospective cohort study conducted from 2009 to 2014 in Korea. After hospitalization, patient platelet count was determined before heparin was prescribed, and all platelet count values obtained during hospitalization were extracted. Suspected HIT was estimated by three 4Ts scores (acute thrombocytopenia, timing onset and other possible causes), which when combined yielded a high probability of HIT. Among 6046 patients enrolled in this study, HIT was suspected in 641 cases (10.6%) and a statistically significant increase in HIT incidence rate was observed for three heparins used (p < 0.001). Dalteparin (HR = 0.55, p = 0.036) and enoxaparin (HR = 0.40, p < 0.001) showed a relatively low HIT incidence rate, compared to unfractionated heparin. Majority of suspected HIT cases (76.9 and 66.7%) occurred in days 8-10 and 5-7 of dalteparin and enoxaparin treatments, respectively. Most of the patients medicated with dalteparin were cancer patients; however, no statistically significant relationship was observed between HIT occurrence and cancer. HIT can cause serious complications, making early diagnosis crucial. Clinical practitioners first prescribing heparin should focus on preventing and detecting complications early by conducting frequent, regular platelet counts before and after heparin administration.

Nadroparin carries a potentially high risk of inducing cutaneous delayed-type hypersensitivity responses.

BACKGROUND: Heparins are widely used for the prophylaxis/treatment of thromboembolic events. As adverse effects, heparin-induced skin lesions occur frequently (in 7.5-39% of patients). Skin lesions may be the only clinical manifestation of life-threatening immune-mediated heparin-induced thrombocytopenia, but are commonly caused by a delayed-type hypersensitivity response [heparin-induced delayed-type hypersensitivity (HIHS)]. Risk factors have not been prospectively identified. OBJECTIVES: To identify possible risk factors for heparin-induced skin lesions from three independent clinical trials in a combined analysis. METHODS: A pooled analysis from prospective studies was performed, and possible risk factors were included in a multiple logistic regression analysis. RESULTS: Obesity (body mass index of > 25), prolonged anticoagulant therapy, prior heparin exposure and younger age (< 55 years) were confirmed as independent risk factors for HIHS. The choice of anticoagulant preparation had the greatest influence. On comparison of dalteparin, enoxaparin, fondaparinux, unfractionated heparin, and nadroparin, the latter was associated with the highest risk of eliciting HIHS (odds ratio of 30.2, 95%CI: 11.7-77.9). CONCLUSIONS: The high risk associated with nadroparin has been validated in controlled trials, and this emphasizes the singularity of each heparin preparation in terms of allergenicity and that individualized anticoagulation is required.

Effects of five treatment regimens on blood loss and blood transfusion in total knee arthroplasty: a preliminary study in China
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OBJECTIVE: Our study is aimed to explore effects of five treatment regimens on blood loss and blood transfusion rate in total knee arthroplasty (TKA) patients. METHODS: 191 TKA patients were divided into the rivaroxaban, nadroparin, and tranexamic acid groups (n = 37 each) as well as into the affected-limb-position and tourniquet group (n = 40 each). A 3-month follow-up after operation was needed for all patients. The total blood loss, hidden blood loss, and dominant blood loss were recorded, and hemoglobin and red blood cell changes, pain and knee swelling degrees, hospital for special surgery (HSS), and American knee society (KSS) knee scores were observed. RESULTS: When compared with the rivaroxaban, nadroparin, and tourniquet groups, TKA patients' dominant blood loss, hidden blood loss, total blood loss, rate and volume of blood transfusion in the tranexamic acid and affected-limb-position groups were significantly decreased. While 7 days after operation, the hemoglobin and red blood cells in the tranexamic acid and affected-limb-position groups were significantly increased. At 1 month and 3 months after operation, when compared with the rivaroxaban, nadroparin, and tourniquet groups, the HSS and KSS scores in the tranexamic acid and affected-limb-position groups were all increased. In comparison with the rivaroxaban, nadroparin, and tourniquet groups, the D-Dimers after operation in the tranexamic acid and affected-limb-position groups were significantly lower. CONCLUSION: These results demonstrated that for TKA patients, the tranexamic acid and affected-limb-position could obviously reduce the blood loss and blood transfusion rate.
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Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic deep vein thrombosis (DVT) of the calf. We aimed to assess whether therapeutic anticoagulation is superior to placebo in patients with symptomatic calf DVT. METHODS: In this randomised, double-blind, placebo-controlled trial, we enrolled low-risk outpatients (without active cancer or previous venous thromboembolic disease) with a first acute symptomatic DVT in the calf from 23 university medical centres or community medical clinics in Canada, France, and Switzerland. We randomly assigned (1:1) patients to receive either the low-molecular-weight heparin nadroparin (171 UI/kg, subcutaneously, once a day) or placebo (saline 0·9%, subcutaneously, once a day) for 6 weeks (42 days). Central randomisation was done using a computer-generated randomisation list, stratified by study centre. Random allocation sequences of variable block size were centrally determined by an independent research clinical centre. Study staff, patients, and outcome assessors (central adjudication committee) were masked to group assignment. Numbered boxes of active drug or placebo were provided to pharmacies in identical packaging. All patients were prescribed compression stockings and followed up for 90 days. The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42 in the modified intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding at day 42. The trial was registered with ClinicalTrials.gov, number NCT00421538. FINDINGS: Between Feb 1, 2008, and Nov 30, 2014, we screened 746 patients, enrolling 259 patients (50% of the prespecified sample size), before the trial steering committee terminated the trial because of expiry of study drug and slow recruitment. The intention-to-treat analysis population comprised 122 patients in the nadroparin group and 130 in the placebo group. There was no significant difference between the groups in the composite primary outcome, which occurred in four patients (3%) in the nadroparin group and in seven (5%) in the placebo group (risk difference -2·1%, 95% CI -7·8 to 3·5; p=0·54). Bleeding occurred in five patients (4%) in the nadroparin group and no patients in the placebo group (risk difference 4·1, 95% CI 0·4 to 9·2; p=0·0255). In the nadroparin group one patient died from metastatic pancreatic cancer and one patient was diagnosed with heparin-induced thrombocytopenia type 2. INTERPRETATION: Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding. Avoidance of systematic anticoagulation for calf DVT could have a substantial impact on individual patients and from a public health perspective. FUNDING: Swiss National Science Foundation, the Programme Hospitalier de Recherche Clinique in France, and the Canadian Institutes of Health Research.

The safety and efficacy of Heparin and Nadroparin compared to placebo in acute ischemic stroke - pilot study.

AIMS: This study aimed to compare the efficacy and safety of heparin and nadroparin in order to provide an additional therapeutic option for patients with acute ischemic stroke in, whom systemic thrombolysis was excluded, or thrombectomy could not be performed. METHODS: We describe a prospective randomized double-blind placebo-controlled pilot study in acute ischemic stroke. The therapeutic window was between 4.5 and 24 h after the onset of stroke. During the first 24 h of treatment, the patients divided into 3 groups received placebo, heparin or nadroparin (in therapeutic doses). During the following 48 h, each patient received nadroparin in the therapeutic dose. 24 h after start of treatment they began taking 100 mg aspirin daily. The primary safety indicator was incidence of complications such as intracerebral or systemic hemorrhage, or death. Efficacy was primarily monitored by the neurological modified Rankin Scale (mRS) at 90 days. RESULTS: There were no signs of intracerebral or systemic bleeding in the cohort of 87 patients. Two patients died - one (3.7%) in the heparin and one (3.8%) in the placebo group due to causes not connected with the treatment. There was a statistically significant difference in mRS on the 90th day between the heparin and placebo groups (21 (80%) vs 13 (50%), P=0.0350) and between the nadroparin and placebo groups (29 (85%) vs 13 (50%), P=0.0031). CONCLUSION: The results show that the treatment with heparin and nadroparin is safe and effective. TRIAL REGISTRATION: Trial is registered in ClinicalTrials.gov: NCT01862978.